rs142883891

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_033380.3(COL4A5):c.1289C>A(p.Ala430Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,208,648 control chromosomes in the GnomAD database, including 12 homozygotes. There are 2,014 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A430T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., 152 hem., cov: 23)

Exomes 𝑓: 0.0053 ( 10 hom. 1862 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.89

Variant links:

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_033380.3

BP4

Computational evidence support a benign effect (MetaRNN=0.00821501).

BP6

Variant X-108591181-C-A is Benign according to our data. Variant chrX-108591181-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 256277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108591181-C-A is described in Lovd as [Pathogenic]. Variant chrX-108591181-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00417 (469/112598) while in subpopulation NFE AF= 0.00582 (310/53233). AF 95% confidence interval is 0.00529. There are 2 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.1289C>A	p.Ala430Asp	missense_variant	20/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.1289C>A	p.Ala430Asp	missense_variant	20/53	1	NM_033380.3		P29400-2
COL4A5	ENST00000483338.1 linkuse as main transcript	c.113C>A	p.Ala38Asp	missense_variant	4/20	1
COL4A5	ENST00000361603.7 linkuse as main transcript	c.1289C>A	p.Ala430Asp	missense_variant	20/51	2		P1	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.00417

AC:

469

AN:

112547

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

152

AN XY:

34721

show subpopulations

Gnomad AFR

AF:

0.000709

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00159

Gnomad ASJ

AF:

0.00977

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00218

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00582

Gnomad OTH

AF:

0.00330

GnomAD3 exomes

AF:

0.00465

AC:

851

AN:

182887

Hom.:

AF XY:

0.00507

AC XY:

342

AN XY:

67505

show subpopulations

Gnomad AFR exome

AF:

0.000229

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00441

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.00563

Gnomad OTH exome

AF:

0.00222

GnomAD4 exome

AF:

0.00527

AC:

5778

AN:

1096050

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

1862

AN XY:

362324

show subpopulations

Gnomad4 AFR exome

AF:

0.000532

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00909

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00427

Gnomad4 FIN exome

AF:

0.00989

Gnomad4 NFE exome

AF:

0.00553

Gnomad4 OTH exome

AF:

0.00529

GnomAD4 genome

AF:

0.00417

AC:

469

AN:

112598

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

152

AN XY:

34782

show subpopulations

Gnomad4 AFR

AF:

0.000707

Gnomad4 AMR

AF:

0.00158

Gnomad4 ASJ

AF:

0.00977

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00219

Gnomad4 FIN

AF:

0.0135

Gnomad4 NFE

AF:

0.00582

Gnomad4 OTH

AF:

0.00326

Alfa

AF:

0.00492

Hom.:

178

Bravo

AF:

0.00337

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00588

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00699

AC:

ExAC

AF:

0.00500

AC:

607

EpiCase

AF:

0.00562

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2019	This variant is associated with the following publications: (PMID: 31144478, 8940267) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	COL4A5: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2019	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ala430Asp in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 1.17% (53/4522) of Finnish chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142883891). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: COL4A5 c.1289C>A (p.Ala430Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 182887 control chromosomes, including 342 hemizygotes and 1 homozygote in the general population (gnomAD). The variant was predominantly at a frequency of 0.0056 within the Non-Finnish European subpopulation in the gnomAD database, including 175 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.21 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive phenotype (0.0046), strongly suggesting that the variant is a benign polymorphism. Six ClinVar submitters have assessed the variant since 2014: five have classified the variant as benign and one as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

X-linked Alport syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.47

.;T;T

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.14

N;N;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

N;N;.

REVEL

Benign

0.20

Sift

Benign

0.29

T;T;.

Sift4G

Benign

0.51

T;T;.

Polyphen

0.0090, 0.0

.;B;B

Vest4

0.070

MVP

0.56

MPC

0.45

ClinPred

0.018

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.44

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over